Ethoxy benzoate esters



2,958,697 Patented Nov. 1, 1960 lice arnoxr BENZOATE rsrnus No Drawing. Filed Apr. 8, 1958, Ser. No. 727,027

6 Claims. (Cl. 260-3265) This invention relates to esters of aminoalcohols. These esters are particularly useful as anesthetics and the invention will be illustrated by description in connection with such use.

Our esters show a very large improvementin the therapeutic index over conventional anesthetics. Thus, we have raised the therapeutic index of 13 found for procaine in our test method to as much as 11003500 for our compounds under comparable conditions. One feature of our compounds, therefore, is their relative freedom from toxicity coupled with unusual effectiveness in anesthetic action. Thus, some of our esters exhibit toxicities as low as one fifth that of procaine. Coupled with this safety factor of decreased toxicity is the high potency as anesthetics which, in individual cases, is 27- 100 times that of procaine. This desirable combination of normally opposed properties will be more clearly refiected in the pharmacological studies reported in Table I.

Briefly stated, our invention comprises the herein described ethoxybenzoate esters of dialkylamino phenylethanols, used as such or in the form of their salts.

We have found that such esters are effective for topical anesthesia. an ethoxyl group in one of the positions of the benzene ring of the esterifying benzoic acid. Thus, similar structures in this category, without an ethoxyl group, or those structures with a methoxyl or halogen instead of an .ethoxyl are not efiective as topical anesthetics.

More specifically, our new compounds are esters or For such efiect, it is necessary to' have salts of esters of tertiary aminoethanols, the general formulae for the alcohols being in which R and R are lower alkyl groups, alike or different, each containing 1-4 carbon atoms, but the sum of the carbon atoms does not exceed five, such radicals including dimethylamino, diethylamino, methylisopropyl- The invention involves esterification of the 2-(disubstituted amino)-1-phenylethanols and Z-(disubstituted amino)-2-phenylethanols with an ethoxy benzoic acid to yield esters having the general formulae These compounds suitably are used in the form of their salts with organic and inorganic acids. Such salts are described later herein. When employed as a local anesthetic, any suitable method of application known in the art may be employed.

EVALUATION AS ANESTHETICS The compounds of this invention were evaluated by the method of Chance and Lobstein, J. PharmacoL, 82, 203 (1944), for determining the median effective dose of a local anesthetic when applied to the cornea of a guinea pig eye.

A known concentration of solution of the local anesthetic is applied to both eyes of a guinea pig and the eyes kept bathed with this solution for 2 minutes. The eyes are then blotted to remove excess solution.

Five minutes later, the eyes are tested for the anesthetic eflfect. A horse hair mounted on a glass rod is used. The hair is pressed against the center of the cornea so that the hair is bent to about the same extent at each application. The hair is applied 10 times to each eye, and the process repeated 5 times for the test (total of prods). The result is reported thus: 100 minus number of blinks=percent anesthesia.

Varying concentrations of the anesthetic agent are used and the percent anesthesia is plotted against concentration. The results are expressed as the ED in mg./ ml. which is the quantity of compound. per milliliter of solution required to eifect 50% anesthesia as established from the plot of concentration vs. percent anesthesia.

The toxicity of the individual compounds was established by administration subcutaneously (s.c-.) to mice, in terms of the minimum dose required to be lethal to mice and expressed as LD in milligrams of compound per kilogram of mouse.

The therapeutic index was then calculated by dividing the LD,,,,,, by the ED the result being a. single figure embracing the anesthetic effectiveness of the compound and its inherent toxicity.

The results are shown in Table I. It will be noted that the compounds show therapeutic indices of 1150- 3580 as compared to the index of 13 found for procaine, the standard local anesthetic, in comparative tests.

In this Table I and elsewhere herein Phis the abbreviation for the monophenyl group.

Table I.Anesthetic potency in guinea pig cornea and toxicity of compounds of the formula (D 1 C-O-CH-CH1N .HX CQHGO L R Therapeutic Index Position of su lninm. -OC:H5 Group R R 11X ing/ml. ing/kg.

min. so mg./kg. mg./ml.

CHa--- GH3- HCl 0. 26 300 1, 150 C 2115-. 0. 52 1, 000 1, 925 CQH5- H61 0. 47 1, 000 2, 130 (CHa)2CH- 0.14 500 3, 580 (CH2)4- 1 HCl 0. 21 400 1,910 (CHz) 4- 1 H01 0. 50 1,000 2, 000 C2Hs C2H5- 0. 54 750 1, 390 Procaine 15.0 200 13 1 For such cyclic amines R and R together represent, with the attached nitrogen a single cyclic radical, here 2 Phenyl group in formula is on carbon 2, not on carbon 1.

The required 2-dialky1amino-l-phenylethanols may be The esters described in this invention are prepared by Indicative of the class of amino alcohols prepared as intermediates in this invention by the general reaction described above are the following compounds listed in the usual techniques from the appropriate intermediates. Suitably, we use an acid chloride with an equivalent proportion or a slight excess of the tertiary aminoethanol, either in the absence of solvent or in the presence of an inert organic solvent such as benzene, toluene, ether or acetonitrile. The acid chloride selected is one containing the ethoxy group in the desired position of the benzoyl chloride used. The tertiary aminoethanol selected is one containing R, R and the phenyl group in the position that appears in the finished product. After a suitable reaction period, either at room temperature or at elevated temperatures controlled by the reflux temperature of the solvent, the reaction mixture is processed to yield the desired product. In most instances, the desired ester of aminoethanol, being basic, appears as the hydrochlo- Table II. ride. This salt is readily isolated and purified by re- Table II.--2-dialkylamino-l-phenylethanols H neonatal-C} R R; Formula B.P.,C. mm. Press. M.P., O.

CHa- 0113- C10H15N0 116417 19 C 2115-- C 2115- CmHmN 0 136-138 10 /CH CHr- CmHmNO 115-116 4 CH3 CHz)4 CnHnNO 57-58 H2)5 CIBH19 66457 (CHa)z-O(CH2)2- CrzHnNOz 77-82 2)o- OHHZINO a- The required 2-dialkylamino-Z-phenylethanols and their salts were prepared by the method of Golumbic (I.

Am. Chem. Soc., 61, 996 (1939)) and are shown in 60 crystallization. Alternatively, if the hydrochloride is not readily crystallizable, it is dissolved in Water, alkalinized to liberate the free base of the ester, and the free ester then extracted into an organic solvent such as ether, benzene, or chloroform, the organic solvent layer evaporated to dryness and the product purified after removal of the solvent by distillation under diminished pressure, the prin- 65 cipal fraction being accepted after characterization by elemental analysis.

Examples of the esters prepared by the general procedures described above are given in Table IV which follows the specific examples which are herein presented to illustrate the present invention.

Salts of the esters are readily prepared by the usual technique, as for example, by neutralizing our esters which are bases, by hydrochloric, hydrobromic, phosphoric, sulfuric, succinic, acetic, or tartaric acid, or other non-toxic acid in a suitable solvent such as alcohol, wa-

ter, ether or benzene. The salts form directly and are collected on a filter or recovered by evaporation.

Quaternary salts are prepared by reaction of the basic esters with such quaternizing agents as methyl iodide, methyl sulfate, methyltoluenesulfonate, ethyl bromide, benzyl bromide, allyl bromide and ethyl bromoacetate.

As more specifically illustrative of the preparation of the compounds contemplated by this invention, the following specific examples of the preparation of specific compounds contemplated by this invention will serve to exemplify the preparation of all compounds, since all of the several compounds contemplated will be prepared in much the same manner with the selection of starting materials required for the production of any particular desired specific compound.

EXAMPLE 1.(2-DIMETHYLAMl1 I-1-PHENYLETHYL o-ETHOXYBENZOATE HYDROCHLORIDE To a cooled solution of o-ethoxybenzoyl chloride (6.1 g., 0.033 mole) in 15 ml. of acetonitrile was slowly added a solution of 5.0 g. (0.03 mole) of Z-dimethylamino-1-phenylethanol in 10 ml. of acetonitrile. An exothermic reaction takes place and crystals begin to form within 30 minutes. After standing 20 hours, 6.8 g. (65%) of product as the hydrochloride was separated, melting at 173-176 C. After recrystallization (ethanol), the melting point was 183184 C.

Analysis.-Calcd. for C H ClNO C, 65.23; H, 6.91; N, 4.00. Found: C, 65.32; H, 6.98; N, 3.84.

EXAMPDE 2.-2-DIETHYLAM1'N0-1-PHENYLE'I"HYL o-ETHOXYBENZOATE (a) To a refluxing solution of 7.4 g. (0.04 mole) of o-ethoxybenzoyl chloride in 100 ml. of benzene was added 7.8 g. (0.04 mole) of 2-diethylamino-l-phenylethanol over a period of 15 minutes. Heating and stirring were continued for 2 hours after addition was complete. On cooling, the somewhat gummy hydrochloride which had separated was dissolved in 100 ml. of water, made basic with 40% aqueous sodium hydroxide while cooling and the resulting free base extracted with five 20 ml. portions of ether. The ether extracts were combined, dried over anhydrous magnesium sulfate and then filtered. After removal of the solvent, distillation yielded 6.4 g. (44%), boiling at 154-156 C. at 0.15 mm.

Analysis.Calcd. for 0 1-1 190 C, 73.87; H, 7.97; N, 4.10. Found: C, 74.06; H, 7.78; N, 4.06.

(b) The same compound was isolated as the hydrochloride when prepared by the method used in Example 1, starting with 81.2 g. (0.44 mole) of o-ethoxybenzoyl chloride, 77.6 g. (0.4 mole) of Z-diethylamino-l-phenylethanol and 400 ml. of acetonitrile. Since the product did not precipitate out, the solvent was removed at diminished pressure and the residue taken up in 400 m1. of boiling methyl ethyl ketone. On cooling, the product crystallized out as the hydrochloride. After refrigerating 3 hours, filtration gave 65.7 g. melting at 111-112 C. The filtrate could be reworked to yield an additional 34 g. of crude product, melting at 103-107 C. A 5 g. sample was purified by recrystallizaton from acetone to give 2.9 g., melting at 113-114 C.

Analysis.-Calcd. for C H ClNO C, 66.74; H, 7.47; N, 3.71. Found: C, 66.70; H, 7.47; N, 3.80.

EXAMPLE 3.-(Z-DIETHYLAMINO-l-PH'ENYLETHYL) p-ETHOXYBENZOATE HYDROCHLORIDE This compound was prepared by the procedure of Example 2a from 7.4 g. (0.04 mole) of p-ethoxybenzoyl chloride, 7.8 g. (0.04 mole) of Z-diethylamino-l-phenylethanol and 100 ml. of dry benzene. The resulting gum was taken up in 30 ml. of ethanol and anhydrous ether was added to yield a solid which was filtered off to give 7 g. of crude product as the hydrochloride melting at 135-145 C. Recrystallization from methyl ethyl ketone gave 4.6 g. (30%) melting at 143-145 C.

Analysis.Calcd. for C H ClNO C, 66.74; H, 7.41; N, 3.71. Found: C, 66.87; H, 7.51; N, 3.85.

The same compound was prepared by the method of Example 1 in 67% yield.

EXAMPLE 4;-(2-PYRROLIDINO-LPHENYLETHYL) P-ETHOXYBENZOATE HYDROCHLORIDE The method of Example 2a was used to prepare this compound using 9.2 g. (0.05 mole) of p-ethoxybenzoyl chloride, 9.6 g. (0.05 mole) of 2-pyrrolidino-1-phenylethanol and ml. of dry benzene. The product precipitated directly from the reaction mixture, yielding 17.6 g. (93%) of the hydrochloride on filtration. Recrystallization from 85 m1. of isopropanol gave 14.1 g. (75%) of product melting at 168-169 C.

Analysis.Calcd. for C H ClNO C, 67.10; H, 6.97; N, 3.73. Found: C, 67.35; H, 7.09; N, 3.94.

EXAMPLE 5.(2-DIETHYLAMlINO-2-PHENYLETHYL) o-ETHOXYBENZOATE This compound was prepared by the procedure of Example 1 using 6.1 g. (0.033 mole) of o-ethoxybenzoyl chloride, 5.8 g. (0.03 mole) of Z-diethylamino-Z-phenylethanol and 50 ml. of acetonitrile. Since the product did not precipitate out, the solvent was distilled off at diminished pressure, the residue taken up in 50 ml. of Water, made basic with 40% aqueous sodium hydroxide and the free base extracted with five 20 ml. portions of ether. These extracts were combined, dried over anhydrous magnesium sulfate, filtered and the solvent removed by distillation which gave 1.6 g. (15%) of product, boiling at 158 C. at 0.1 mm.

Analysis.-Calcd. for C H NO C, 73.87; H, 7.97; N, 4.10. Found: C, 73.35; H, 8.25; N, 4.38.

EXAMPLE 6.- (2-PYRROLIDINO-1-PHENYLETHYL) o-ETHOXYBENZOATE HYDROCHLORIDE This compound was prepared by the procedure of Example 4 using o-ethoxybenzoyl chloride, 9.6 g. (0.05 mole) of 2-pyrrolidino-l-phenylethanol and ml. of benzene. Filtration of the precipitated product and recrystallization from ethanol and then from isopropanol gave 28% of product, M.P. 186187 C.

Analysis.Calcd. for C H ClNO C, 67.10; H, 6.97; N, 3.73. Found: C, 66.76; H, 7.05; N, 3.72.

SUMMARY OF BASIC ESTERS PREPARED With the selection of reactants as described earlier herein, to give the values desired for the various Rs herein and With the technique illustrated in Examples 1-6 above, we have made the basic esters and their salts shown in Table IV.

Position of B.

Group Orth0 Ortho Ortho- Para Ortho- O Ortho- Para Orthoa...

For 1 and 2 see Table I.

THERAPEUTIC COMPOSITIONS as a topical anesthetic agent, containing 5.0% active ingredient:

Stir, with heating to 70 C. (mixture A)- of the Water 286.1

Add mixture B to mixture A at 70 C. Stir and cool to room temperature. It is then packaged cold into tubes or jars.

Formula B.-Using the free base of the topical anesthetic agent.

For the preparation of 500 g. of ointment to be used as a topical anesthetic agent, containing 5.0% of the active ingredient:

Stir, with heating to 70 C. (mixture C) G. Stearic acid 100 Glycerol monostearate 20 Sorbitan monopalmitate 20 Beeswax 10 Methyl p-hydroxybenzoate 0.25 Propyl p-hydroxybenzoate 0.15 (2 diethylamino 1 phenylethyl) o ethoxybenzoate 25 .0 Stir, with heating to 70 C. (mixture D)- Water 286.10 Sobitol 70% 28.5 Polyoxyethylene sorbitan monopalmitate 10.0

Add mixture D to mixture C at 70 C. Stir and cool to room temperature. It is then packaged cold into tubes or jars.

Ointments of this type have shown decided anesthetic response when evaluated in human volunteers.

Concentration of the active ingredient may vary from 05-20%.

It is to be understood that it is intended to cover all changes an modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

We claim:

1. Ethoxybenzoate ester compounds of dialkylamino phenylethanols selected from the group consisting of ethoxybenzoate esters having the formula:

and nontoxic mineral acid salts thereof in which -NRR is selected from the group consisting of dialkylamino radicals aggregating from two to five carbon atoms and the pyrrolidino radical, one of R and R is hydrogen and the other is phenyl.

2. The compound 3. The compound 4. The compound 5. The compound 6. The compound References Cited in the file of this patent UNITED STATES PATENTS Forneau Aug. 21, 1906 Cusic Feb. 17, 1953 OTHER REFERENCES 

1. ETHOXYBENZOATE ESTER COMPOUNDS OF DIALKYLMINO PHENYLETHANOLS SELECTED FROM THE GROUP CONSISTING OF ETHOXYBENZOATE ESTERS HAVING THE FORMULA:
 5. THE COMPOUND 